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IACS-6274 With or Without Pembrolizumab for the Treatment of Advanced Solid Tumors

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ClinicalTrials.gov Identifier: NCT05039801
Recruitment Status : Recruiting
First Posted : September 10, 2021
Last Update Posted : September 13, 2021
Sponsor:
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
This phase I trial tests the safety, side effects, and best dose of IACS-6274 with or without pembrolizumab in treating patients with solid tumors that have spread to other places in the body (advanced). IACS-6274 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving IACS-6274 with or without pembrolizumab may help to control the disease.

Condition or disease Intervention/treatment Phase
Advanced Endometrial Carcinoma Advanced Head and Neck Squamous Cell Carcinoma Advanced Malignant Solid Neoplasm Advanced Melanoma Advanced Ovarian Clear Cell Adenocarcinoma Chondrosarcoma Clinical Stage III Cutaneous Melanoma AJCC v8 Clinical Stage IV Cutaneous Melanoma AJCC v8 Pathologic Stage III Cutaneous Melanoma AJCC v8 Pathologic Stage IIIA Cutaneous Melanoma AJCC v8 Pathologic Stage IIIB Cutaneous Melanoma AJCC v8 Pathologic Stage IIIC Cutaneous Melanoma AJCC v8 Pathologic Stage IIID Cutaneous Melanoma AJCC v8 Pathologic Stage IV Cutaneous Melanoma AJCC v8 Refractory Endometrial Carcinoma Refractory Head and Neck Squamous Cell Carcinoma Refractory High Grade Ovarian Serous Adenocarcinoma Refractory Melanoma Refractory Ovarian Clear Cell Adenocarcinoma Stage III Ovarian Cancer AJCC v8 Stage III Uterine Corpus Cancer AJCC v8 Stage IIIA Ovarian Cancer AJCC v8 Stage IIIA Uterine Corpus Cancer AJCC v8 Stage IIIA1 Ovarian Cancer AJCC v8 Stage IIIA2 Ovarian Cancer AJCC v8 Stage IIIB Ovarian Cancer AJCC v8 Stage IIIB Uterine Corpus Cancer AJCC v8 Stage IIIC Ovarian Cancer AJCC v8 Stage IIIC Uterine Corpus Cancer AJCC v8 Stage IIIC1 Uterine Corpus Cancer AJCC v8 Stage IIIC2 Uterine Corpus Cancer AJCC v8 Stage IV Ovarian Cancer AJCC v8 Stage IV Uterine Corpus Cancer AJCC v8 Stage IVA Ovarian Cancer AJCC v8 Stage IVA Uterine Corpus Cancer AJCC v8 Stage IVB Ovarian Cancer AJCC v8 Stage IVB Uterine Corpus Cancer AJCC v8 Drug: Glutaminase Inhibitor IPN60090 Biological: Pembrolizumab Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of oral glutaminase inhibitor IPN60090 (IACS-6274) as monotherapy (Part A) and in combination therapy with pembrolizumab (Part B).

II. To determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of IACS-6274 in combination therapy with pembrolizumab (Part B). (For Dose Escalation Only)

SECONDARY OBJECTIVES:

I. To assess the preliminary antitumor activity of IACS-6274 as monotherapy (Part A) and in combination with pembrolizumab (Part B) in patients with or without biomarker selected tumor types.

II. To characterize the pharmacokinetics (PK) and pharmacodynamic (PD) profile of IACS-6274 as a monotherapy (Part A) and in combination with pembrolizumab (Part B).

III. To evaluate biomarkers of patient stratification and correlate them with clinical outcome.

EXPLORATORY OBJECTIVE:

I. To collect biobank samples for potential future analysis of biomarkers (optional, informed consent required).

OUTLINE: This is a dose-escalation study of IACS-6274 followed by a dose-expansion study. Patients are assigned to 1 of 2 parts.

PART A: Patients receive IACS-6274 orally (PO) twice daily (BID) on days 1-21. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity.

PART B: Patients receive IACS-6274 PO BID on days 1-21 and pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days. Part B patients are also followed up at 60 and 90 days.

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Study Type : Interventional
Estimated Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Open-Label, Dose-Escalation and Dose-Expansion Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Anti-Tumor Activity of IACS-6274 as Monotherapy and in Combination in Patients With Advanced Solid Tumors
Actual Study Start Date : September 9, 2021
Estimated Primary Completion Date : May 29, 2026
Estimated Study Completion Date : May 29, 2026


Arm Intervention/treatment
Experimental: Part A (IACS-6274)
Patients receive IACS-6274 PO BID on days 1-21. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity.
Drug: Glutaminase Inhibitor IPN60090
Given PO
Other Names:
  • IPN 60090
  • IPN-60090
  • IPN60090

Experimental: Part B (IACS-6274, pembrolizumab)
Patients receive IACS-6274 PO BID on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity.
Drug: Glutaminase Inhibitor IPN60090
Given PO
Other Names:
  • IPN 60090
  • IPN-60090
  • IPN60090

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475




Primary Outcome Measures :
  1. Incidence of adverse events (AEs) [ Time Frame: Up to 90 days ]
    Will be assessed by the rate of dose limiting toxicities at each dose level in the dose escalation, and the rate of AEs and the rate of Grade 3 and higher AEs in the dose escalation and dose expansion. All AEs will be coded according to the latest version of Medical Dictionary for Regulatory Activities and National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Provision of written informed consent prior to any study related procedures
  • Patients >= 18 years of age at the time of study entry who agree to participate by giving written informed consent prior to participation in any study related activities
  • Histologically or cytologically confirmed advanced solid tumors, specifically,

    • Dose Escalation and Dose Expansion may include:

      • Patients with tumors with actionable KEAP1/NFE2L2/STK11/NF1 mutations
      • Patients with low ASNS expression levels (high-grade serous ovarian carcinoma [HGSOC] or endometrial cancer)
      • Post-immunotherapy (IO) melanoma (minimum treatment duration of prior PD-1 or PD-L1-containing regimen is 12 weeks [or equivalent of 2 response evaluations])
    • Dose Escalation may also include:

      • Patients with post-platinum HNSCC
      • Patients with chondrosarcoma
      • Patients with ARID1A mutant clear cell ovarian cancer Note: all biomarker mutations/expression levels must be confirmed prior to study treatment
  • Patients must have received at least one line of therapy for advanced stage disease and be refractory or ineligible to available existing therapy(ies) known to provide clinical benefit for their condition
  • Prior treatment with chemotherapy, radiotherapy, immunotherapy or any investigational therapies must have been completed at least 3 weeks or at least five half-lives, whichever is shorter, before the study drug administration, and all adverse events (AEs) (excluding alopecia and peripheral neuropathy) have either returned to =< grade 1 or stabilized
  • Fresh and/or archival tumor tissue from the biopsy obtained between the completion of the most recent line of treatment until study entry must be available for mutation and biomarker analysis. Patients should not be put at undue risk to obtain fresh tumor biopsy. If available, archival tumor tissue from time of initial diagnosis will be collected in addition to the most recent biopsy (archival and/or fresh)
  • Measurable or non-measurable evaluable disease as defined per the Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 (or immune-related RECIST [iRECIST] for Part B only)
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1
  • Absolute neutrophil count (ANC) >= 1500/mL
  • Platelets >= 100,000/mL
  • Hemoglobin >= 9 g/dL
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) and/or creatinine clearance > 40 mL/min. Actual body weight should be used for calculating creatinine clearance using the Cockroft-Gault equation (except for patients with body mass index > 30 kg/m^2 when the lean body weight should be used)
  • Serum total bilirubin =< 1.5 x ULN (with the exception of patients with known Gilbert's syndrome: serum total bilirubin must be < 3 x ULN in these patients)
  • Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) and alanine aminotransferase (serum glutamic pyruvic transaminase) =< 2.5 x ULN or =< 5 x ULN for patients with liver metastases)
  • Left ventricular ejection fraction >= 50%
  • Female patients are eligible to enter and participate in the study if they are of:

    • Non-childbearing potential (physiologically incapable of becoming pregnant), including any female who:

      • Has had a hysterectomy, OR
      • Has had a bilateral oophorectomy, OR
      • Has had a bilateral salpingectomy, OR
      • Is postmenopausal (total cessation of menses for >= 2 years, or follicle-stimulating hormone >= 50 IU/L)
    • Childbearing potential, but with a negative serum pregnancy test at screening (within 7 days of the first investigational medicinal product [IMP] administration), is not breastfeeding, and uses highly effective contraception at study entry and throughout the study until 90 days after the last administration. Highly effective contraceptive methods include:

      • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (for example oral, intravaginal, transdermal)
      • Progestogen-only hormonal contraception associated with inhibition of ovulation (for example oral, implantable, injectable)
      • Intrauterine device
      • Intrauterine hormone-releasing system
      • Bilateral tubal occlusion
      • Male partner has had a vasectomy
  • Male patients are eligible to enter and participate in the study if they agree to use effective methods of contraception during the study treatment period and for at least 90 days after the last dose of investigational product

Exclusion Criteria:

  • Prior malignancy within the previous 2 years except for locally curable cancers that have been cured, such as basal or squamous cell skin cancer, or carcinoma in situ of the cervix, breast or bladder
  • Known primary central malignancy or symptomatic central nervous system metastasis(es)

    • Note: Patients with stable, previously treated brain metastases may participate if neurologic symptoms have resolved, patients have been off steroids for at least 7 days, and there is no evidence of disease progression by imaging for at least 2 weeks before the first dose of study treatment
  • Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 2 weeks of the first dose of study drug
  • Uncontrolled, significant intercurrent or recent illness including, but not limited to, the following cardiac conditions:

    • Any unstable cardiac arrhythmia within 6 months prior to enrolment
    • Prolongation of the Fridericia corrected QT (QTcF) interval defined as > 450 ms for males and > 470 ms for females
    • History of any of the following cardiovascular conditions within 6 months of enrolment:

      • Cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery
      • Bypass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure, as defined by the New York Heart Association
  • Major surgical intervention within 28 days before study drug administration
  • Significant acute or chronic infections
  • Any psychiatric condition that would prohibit the understanding or rendering of informed consent
  • Treatment with strong cytochrome P450 (CYP450) subtype 3A4 (CYP3A4) inducers (including St John's wort) and inhibitors (including grapefruit juice) within 7 days of the first dose of study drug
  • Treatment with strong CYP450 subtype 2D6 (CYP2D6) inhibitors within 7 days of the first dose of study drug
  • Radiotherapy within 4 weeks prior to the start of study drug. Palliative radiotherapy for symptomatic control is acceptable if completed at least 2 weeks prior to study drug administration and no additional radiotherapy for the same lesion is planned
  • Underlying medical conditions that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or AEs
  • History of allergic reactions attributed to compounds of similar chemical or biological composition to any of the compounds in the study
  • Known alcohol or drug abuse
  • Legal incapacity or limited legal capacity
  • Inability to swallow oral medications (capsules and tablets) without chewing, breaking, crushing, opening or otherwise altering the product formulation. Patients should not have gastrointestinal illnesses that would preclude the absorption of IACS-6274, which is an oral agent
  • Patients unwilling to comply with protocol requirements related to the assigned part
  • PART B (DOSE ESCALATION AND DOSE EXPANSION) SPECIFIC EXCLUSION CRITERIA
  • Autoimmune disease that might deteriorate when receiving an immune-stimulatory agent, or immunodeficiencies
  • Known severe hypersensitivity reactions to monoclonal antibodies, any history of anaphylaxis, or uncontrolled asthma (that is, three or more features of partially controlled asthma)
  • Prior organ transplantation, including allogeneic stem cell transplantation
  • Patient has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05039801


Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Timothy A. Yap    713-563-1930    tyap@mdanderson.org   
Principal Investigator: Timothy A. Yap         
Sponsors and Collaborators
M.D. Anderson Cancer Center
Investigators
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Principal Investigator: Timothy A Yap M.D. Anderson Cancer Center
Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT05039801    
Other Study ID Numbers: 2021-0265
NCI-2021-09063 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2021-0265 ( Other Identifier: M D Anderson Cancer Center )
national cancer institute
First Posted: September 10, 2021    Key Record Dates
Last Update Posted: September 13, 2021
Last Verified: September 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Ovarian Neoplasms
Carcinoma
Melanoma
Carcinoma, Squamous Cell
Adenocarcinoma
Carcinoma, Ovarian Epithelial
Squamous Cell Carcinoma of Head and Neck
Skin Neoplasms
Endometrial Neoplasms
Chondrosarcoma
Cystadenocarcinoma, Serous
Adenocarcinoma, Clear Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Nevi and Melanomas
Neoplasms, Squamous Cell
Endocrine Gland Neoplasms
Neoplasms by Site
Ovarian Diseases
Adnexal Diseases
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Head and Neck Neoplasms